Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system. Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. Furthermore, glutamate is at the centre of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.
Glutamate mediates synaptic neurotransmission through the activation of ionotropic glutamate receptors channels (iGluRs), and the NMDA, AMPA and kainate receptors which are responsible for fast excitatory transmission (Kew and Kemp Psychopharmacol., (2005), 179:4-29). In addition, glutamate activates metabotropic glutamate receptors (mGluRs) which have a more modulatory role that contributes to the fine tuning of synaptic efficacy.
Glutamate activates the mGluRs through binding to the large extracellular amino terminal domain of the receptor, herein called the orthosteric binding site. This binding induces a conformational change in the receptor which results in the activation of the G protein and intracellular signaling pathways. mGluR5 and NMDA receptors are co-expressed in hippocampus, cortex and striatum. mGluR5 potentiates NMDA receptor function via a PKC- and Src-dependent mechanism. Blockade of mGluR5 or NMDA receptors impairs cognitive function whereas activation of mGluR5 or NMDA receptors normalizes amphetamine-disrupted pre-pulse inhibition (PPI). Stimulation of mGluR5 receptors is postulated to normalize the NMDA receptor hypofunction which is hypothesised to occur in schizophrenia. An mGluR5 positive allosteric modulator (PAM) may have beneficial effects on cognition and positive and negative symptoms of schizophrenia, and cognitive deficits in various forms of dementia and mild cognitive impairment.
To date, most of the available pharmacological tools targeting mGluRs are orthosteric ligands which cross-react with several members of the family as they are structural analogs of glutamate and have limited bioavailability (Schoepp D. D. et al. Neuropharmacology (1999), 38(10), 1431-1476). A new avenue for developing selective compounds acting at mGluRs is to identify molecules that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved glutamate binding site. Positive allosteric modulators of mGluRs have emerged recently as novel pharmacological entities offering this attractive alternative. This type of molecule has been discovered for several mGluRs (reviewed in Mutel (2002) Expert Opin. Ther. Patents 12:1-8).
WO 2008/012010 A1 (UCB Pharma, S.A.) published on Jan. 31, 2008 discloses fused oxazoles and thiazoles as Histamine H3-receptor ligands and US 2010/0081690 (Addex Pharma, S.A.) published on Apr. 1, 2010 discloses oxazole derivatives as positive allosteric modulators of mGluR5.
Unfortunately, there is a scarcity of selective positive allosteric modulators for the mGluR5 receptor. Further, conventional mGluR5 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral bioavailability. Therefore, there remains a need for methods and compositions that overcome these deficiencies and that effectively provide selective positive allosteric modulators for the mGluR5 receptor.